A compound directed against S6K1 hampers fat mass expansion and mitigates diet-induced hepatosteatosis
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ABSTRACT:
PROVIDER: PRJNA794149 | ENA |
REPOSITORIES: ENA
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Project description:Imbalanced mTORC1-S6K1 engages signalling cascades related to obesity and fatty liver. Here, we set up to assess the therapeutic blockage of the ribosomal protein S6 kinase 1 (S6K1) in diet-induced obese (DIO) mice challenged with LY2584702 (LY) tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumours. To characterize the ability of LY in counteracting obesity and diet-induced disturbances, DIO male mice were challenged every 12 h by oral gavage with LY in treatments lasting 12 and 4 weeks. We show that diminished S6K1 activity in mice treated with LY hampers fat mass expansion and ameliorates dyslipidaemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver performance. Accordingly, impaired mTORC1 signalling in fat (decreased) and liver (increased) co-segregated with defective epithelial-mesenchymal transition, being prominent a decreased expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures, while hypertriglyceridemia and hepatic steatosis were improved in treatments of 12 and 4 weeks. This study provides new insights into the therapeutic intervention of S6K1 signalling, and opens a promising avenue for prevalent metabolic diseases.
2022-08-01 | GSE193028 | GEO
Project description:The ribosomal protein S6 kinase 1 (S6K1) is a relevant effector downstream of the mammalian target of rapamycin complex 1 (mTORC1), best known for its role in the control of lipid homeostasis. Consistent with this, mice lacking the S6k1 gene have a defect in their ability to induce the commitment of fat precursor cells to the adipogenic lineage, which contributes to a significant reduction of fat mass. Here, we assess the therapeutic blockage of S6K1 in diet-induced obese mice challenged with LY2584702 tosylate, a specific oral S6K1 inhibitor initially developed for the treatment of solid tumors. We show that diminished S6K1 activity hampers fat mass expansion and ameliorates dyslipidemia and hepatic steatosis, while modifying transcriptome-wide gene expression programs relevant for adipose and liver function. Accordingly, decreased mTORC1 signaling in fat (but increased in the liver) segregated with defective epithelial-mesenchymal transition and the impaired expression of Cd36 (coding for a fatty acid translocase) and Lgals1 (Galectin 1) in both tissues. All these factors combined align with reduced adipocyte size and improved lipidomic signatures in the liver, while hepatic steatosis and hypertriglyceridemia were improved in treatments lasting either 3 months or 6 weeks.
| S-EPMC9431684 | biostudies-literature
Project description:To elucidate the role of S6K1 in human brain development, we performed next-generation sequencing-based genomweide analysis of S6K1 knockout (KO) human embryonic stem cells (ESCs) and brain organoids. Development/differentiation-related genes were highly enriched in DEGs of S6K1 KO hESCs compared to WT hESCs. Single cell transcriptomic analysis showed unusual retinal cell development in S6K1-depleted brain organoids, thereby reducing neural populations. Furthermore, we generated brain organoids containing both WT and S6K1 KO cells and then isolated them after completing differentiation to compare the feature of each portion grown in mixed condition. ATAC sequencing analysis of each portion in mixed brain organoids displayed no significant differences in retinal cell marker gene transcriptomes between WT and S6K1 KO portions, while chromatin accessibility of neural-specific genes were lower in S6K1 KO portion than WT. Collectively, this study revealed that S6K1 plays dual role in human brain development; suppression of retinal lineage specification and production of mature neurons through non-cell autonomous and cell autonomous action, respectively.
2025-09-25 | GSE214340 | GEO
Project description:To elucidate the role of S6K1 in human brain development, we performed next-generation sequencing-based genomweide analysis of S6K1 knockout (KO) human embryonic stem cells (ESCs) and brain organoids. Development/differentiation-related genes were highly enriched in DEGs of S6K1 KO hESCs compared to WT hESCs. Single cell transcriptomic analysis showed unusual retinal cell development in S6K1-depleted brain organoids, thereby reducing neural populations. Furthermore, we generated brain organoids containing both WT and S6K1 KO cells and then isolated them after completing differentiation to compare the feature of each portion grown in mixed condition. ATAC sequencing analysis of each portion in mixed brain organoids displayed no significant differences in retinal cell marker gene transcriptomes between WT and S6K1 KO portions, while chromatin accessibility of neural-specific genes were lower in S6K1 KO portion than WT. Collectively, this study revealed that S6K1 plays dual role in human brain development; suppression of retinal lineage specification and production of mature neurons through non-cell autonomous and cell autonomous action, respectively.
2025-09-25 | GSE214339 | GEO
Project description:To elucidate the role of S6K1 in human brain development, we performed next-generation sequencing-based genomweide analysis of S6K1 knockout (KO) human embryonic stem cells (ESCs) and brain organoids. Development/differentiation-related genes were highly enriched in DEGs of S6K1 KO hESCs compared to WT hESCs. Single cell transcriptomic analysis showed unusual retinal cell development in S6K1-depleted brain organoids, thereby reducing neural populations. Furthermore, we generated brain organoids containing both WT and S6K1 KO cells and then isolated them after completing differentiation to compare the feature of each portion grown in mixed condition. ATAC sequencing analysis of each portion in mixed brain organoids displayed no significant differences in retinal cell marker gene transcriptomes between WT and S6K1 KO portions, while chromatin accessibility of neural-specific genes were lower in S6K1 KO portion than WT. Collectively, this study revealed that S6K1 plays dual role in human brain development; suppression of retinal lineage specification and production of mature neurons through non-cell autonomous and cell autonomous action, respectively.
2025-09-25 | GSE232448 | GEO
Project description:To systematically identify the function of S6K1 and S6K2 in glioblastoma cells, LN229 cells were stably transduced with Cas9, control non-targeting sgRNA (sgNT), or sgRNAs targeting S6K1 or S6K2. The cells were then transiently transfected with non-targeting siRNAs (siNT), or siRNA pools targeting S6K1 or S6K2. RNA sequencing was performed to compare cellular responses to inactivation of single or combination S6 kinases.
2024-08-28 | GSE196591 | GEO
Project description:Loss of Tsc1 in the kidneys gives rise to rapid polycystogenesis and kidney failure due to the hyperactivation of mTOR complex I (mTORC1). One of the major downstream targets of mTORC1 is S6K1, which is responsible for driving many of the effector functions of mTOR. Strikingly, the loss of S6k1 in the context of hyperactivated mTOR is sufficient to reverse the generation of polycystic kidneys. In an effort to uncover novel direct S6k1 substrates involved in the generation of cystic kidneys, we generated Tsc1-null and Tsc1/S6k1-double null murine inner medullary collecting duct (iMCD3) cell lines using CRISPR/Cas9. Using these two cell lines, we conducted a phosphoproteome screen to search for novel candidates. Using a combination of antibody-motif enrichment and metal affinity enrichment, we provide a comprehensive phosphoproteome profile between these two genotypes.
2020-08-11 | PXD014832 | Pride
Project description:Expression profiles of ZR751 breast cancer cells after downregulation of S6K1, S6K2 and S6K1+S6K2. Triplicates of control, S6K1siRNA, S6K2siRNA and S6K1+S6K2siRNA, in total twelve samples.
2015-12-09 | E-GEOD-75813 | biostudies-arrayexpress
Project description:Expression profiles of ZR751 breast cancer cells after downregulation of S6K1, S6K2 and S6K1+S6K2.
2015-12-09 | GSE75813 | GEO
Project description:We examined the transcript changes in long-lived S6K1-/- female mice compared to wild type controls.
2009-09-04 | E-MEXP-2320 | biostudies-arrayexpress